Pyridazinones are components of numerous pharmacologically diverse compounds. Thyroxin analogs have been reported, which contain, inter alia, the pyridazinone ring, and these analogs were reported to lower plasma cholesterol without the cardio-stimulatory effect of thyroxine (A. H. Underwood et al. Nature 1986 324(6096):425-429; P. D. Leeson et al. J. Med Chem 1989 32(2):320-326 and P. D. Leeson et al. EP 0188351). Oxo-pyridazinylmethyl substituted tyrosines that are selective antagonists for the haematopoietic phosphatase SH2 domain have been reported (D. J. Dunnington, WO9624343, WO 9702023 and WO9702024). WO2001085670 (H. Shiohara et al.) discloses related pyridazinone-containing malonamide derivatives useful for treating circulatory diseases. EP 810218 (D. A. Allen et al.) discloses benzoyl substituted benzyl-pyridazinone compounds which are cyclooxygenase inhibitors and potential antiinflammatory or analgesic compounds. U.S. Ser. No. 60/457,144 (J. P. Dunn et al.), hereby incorporated by reference in its entirety, discloses pyridazinone compounds useful to inhibit HIV reverse transcriptase.
The pyridazinone ring can be introduced into a molecule by alkylation of a phenyl acetic acid derivative 4 (R═CO2R4a) or a phenylacetonitrile 4 (R═CN) with 3,6-dichloropyrazine (5a; M. M. Rodgers and J. P. English, U.S. Pat. No. 2,371,086). Acid- or based catalyzed hydrolysis of the ester or nitrile 6 (R═CN or COR4a) affords the corresponding carboxylic acid which can be isolated if desired, or subjected to acid-catalyzed decarboxylation in situ. Hydrolysis of the chloropyridazine affords the pyridazinone 7. (P. D. Leeson and J. C. Emmett, J. Chem. Soc. Perkin I 1988 3085; D. A. Allen et al., EP 810218). While this process is often satisfactory with 5a wherein both chlorine carbon bonds are chemically equivalent, unsymmetrical dichloropyridazinones such as 5b (Ra=alkyl) produce a mixture of regioisomers which are often difficult to separate. Alternately, pyridazinones are formally equivalent to 4-oxo-butenoic acid amides and an appropriately substituted 4-oxo-butenoic acid derivative can be converted to pyridazinones by exposure to hydrazine hydrate.

The present process affords a convenient alternate route to 4-alkylpyridazinones 7 (Ra=alkyl) in which the regioisomer problem created by the alkyl substituent is conveniently resolved in an early convergent step in the process. The present invention further affords a convenient route tro 3-(hetero)aryloxy-2-fluoro-phenylacetic acid compounds which are useful intermediates to prepare HIV reverse transcriptase inhibitors. Moreover, the present process permits the regiospecific elaboration of four contiguous aryl carbons.